Heterologous regulation of CXCR4 lysosomal trafficking
| Autor: | Mudassir S. Ali, M. Rose Rogers, Sarah A. Mahn, Adriano Marchese, Adriana Caballero |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Receptors CXCR4 Ubiquitin-Protein Ligases media_common.quotation_subject Biochemistry CXCR5 03 medical and health sciences Chemokine receptor Humans Internalization Molecular Biology Protein Kinase C Protein kinase C G protein-coupled receptor media_common 030102 biochemistry & molecular biology biology Chemistry Ubiquitination Cell Biology G-Protein-Coupled Receptor Kinases Chemokine CXCL13 Chemokine CXCL12 Ubiquitin ligase Cell biology Enzyme Activation Repressor Proteins Protein Transport HEK293 Cells 030104 developmental biology Proteolysis biology.protein Tetradecanoylphorbol Acetate Phosphorylation Signal transduction Lysosomes HeLa Cells Signal Transduction |
| Zdroj: | J Biol Chem |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra118.005991 |
| Popis: | G protein–coupled receptor (GPCR) signaling is regulated by members of the protein kinase C (PKC) and GPCR kinase (GRK) families, although the relative contribution of each to GPCR function varies among specific GPCRs. The CXC motif receptor 4 (CXCR4) is a member of the GPCR superfamily that binds the CXC motif chemokine ligand 12 (CXCL12), initiating signaling that is subsequently terminated in part by internalization and lysosomal degradation of CXCR4. The purpose of this study is to define the relative contribution of PKC and GRK to CXCR4 signaling attenuation by studying their effects on CXCR4 lysosomal trafficking and degradation. Our results demonstrate that direct activation of PKC via the phorbol ester phorbol 12-myristate 13-acetate (PMA) mimics CXCL12-mediated desensitization, internalization, ubiquitination, and lysosomal trafficking of CXCR4. In agreement, heterologous activation of PKC by stimulating the chemokine receptor CXCR5 with its ligand, CXCL13, also mimics CXCL12-mediated desensitization, internalization, ubiquitination, and lysosomal degradation of CXCR4. Similar to CXCL12, PMA promotes PKC-dependent phosphorylation of serine residues within CXCR4 C-tail that are required for binding and ubiquitination by the E3 ubiquitin ligase AIP4 (atrophin-interacting protein 4). However, inhibition of PKC activity does not alter CXCL12-mediated ubiquitination and degradation of CXCR4, suggesting that other kinases are also required. Accordingly, siRNA-mediated depletion of GRK6 results in decreased degradation and ubiquitination of CXCR4. Overall, these results suggest that PKC and GRK6 contribute to unique aspects of CXCR4 phosphorylation and lysosomal degradation to ensure proper signal propagation and termination. |
| Databáze: | OpenAIRE |
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